Involvement of Heat Shock Protein A4/Apg-2 in Refractory Inflammatory Bowel Disease

Adachi, Teppei; Sakurai, Toshiharu; Kashida, Hiroshi; Mine, Hiromasa; Hagiwara, Satoru; Matsui, Shigenaga; Yoshida, Kōji; Nishida, Naoshi; Watanabe, Tomohiro; Itoh, Katsuhiko; Fujita, Jun; Kudo, Masatoshi

doi:10.1097/mib.0000000000000244

Cited by 27 publications

(37 citation statements)

References 35 publications

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“…Bmi1 expression levels were increased in patients with refractory IBD associated with long-term inflammation compared with those in controls or IBD patients in remission [7] . Immunohistochemistry was performed to identify the cells expressing Bmi1 in the human intestine.…”

Section: Increased Bmi1 Expression Seen In Refractory Ibd Predicts Pomentioning

confidence: 88%

“…4 a-c). The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD [7] , suggesting that Bmi1 expression might be related to increased risk for CAC. Consistently, Bmi1 expression was increased in 9 of 10 CACs we examined.…”

Section: Bmi1 Expression Is Enhanced In Human Cacmentioning

confidence: 98%

“…In the colonic mucosa of IBD patients, longstanding intestinal inflammation increases the expression of stress response proteins including CIRP, RBM3, and HSPA4, whose expression correlates significantly with Bmi1 expression [6][7][8] . Therefore, we explored whether an association exists between Bmi1 expression and cytokine production in IBD patients.…”

Section: Association Between Bmi1 and Cytokines In The Colonic Mucosamentioning

confidence: 99%

“…induces stress response proteins such as cold-inducible RNA-binding protein (CIRP), heat shock protein A4 (HSPA4), and RNA-binding motif protein 3 (RBM3), which regulate apoptosis of inflammatory or epithelial cells and expansion of stem cells, leading to the development of CAC [6][7][8] . In addition, HSPA4 expression could predict poor therapeutic response to steroids in IBD patients.…”

mentioning

confidence: 99%

“…In the context of chronic inflammation, immune responses would affect proliferation of stem cells and increase the expression of stem cell markers [10] . The expression of stress response proteins and gankyrin that functionally link between chronic inflammation and tumorigenesis in IBD is significantly correlated with that of the stem cell marker Bmi1 [6][7][8][9] . The polycomb group protein Bmi1 is frequently overexpressed in human sporadic colorectal cancer, and the degree of upregulation correlates with disease progression and is predictive of poor patient survival [11] .…”

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confidence: 99%

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Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease

et al. 2017

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Background: Although the stem cell marker Bmi1 is overexpressed in many malignancies, its role in inflammation-associated cancer is unclear. Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Methods: To assess the involvement of Bmi1 in the development of CAC, we analyzed the gene expression of colon tissues collected from 111 patients with IBD and CAC. Results: In the colonic mucosa of patients with ulcerative colitis, the expression of Bmi1 correlated significantly with the expression of inflammatory cytokines such as IL-6, IL-17, IL-23, and tumor necrosis factor α (TNF-α). In the colonic mucosa of patients with Crohn's disease, the expression of Bmi1 correlated significantly with the expression of TNF-α and IL-23. The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD, suggesting that Bmi1 expression might be related to increased cancer risk. In addition, patients with high Bmi1 expression showed significantly lower response rates upon subsequent anti-TNF-α therapy as compared to patients with low Bmi1 expression. In human CAC specimens, the expression of Bmi1 was upregulated in nontumor tissues as well as tumors. Conclusions: Bmi1 expression is related to a refractory clinical course of IBD and upregulated in refractory IBD and CAC. Measurement of Bmi1 expression is a promising approach for the advanced treatment and personalized management of IBD patients.

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Section: Increased Bmi1 Expression Seen In Refractory Ibd Predicts Pomentioning

confidence: 88%

Section: Bmi1 Expression Is Enhanced In Human Cacmentioning

confidence: 98%

Section: Association Between Bmi1 and Cytokines In The Colonic Mucosamentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease

et al. 2017

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Hsp74/14‐3‐3σ Complex Mediates Centrosome Amplification by High Glucose, Insulin, and Palmitic Acid

Lü

Wang

et al. 2019

Proteomics

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It has been reported recently that type 2 diabetes promotes centrosome amplification via 14-3-3σ /ROCK1 complex. In the present study, 14-3-3σ interacting proteins are characterized and their roles in the centrosome amplification by high glucose, insulin, and palmitic acid are investigated. Co-immunoprecipitation in combination with MS analysis identified 134 proteins that interact with 14-3-3σ , which include heat shock 70 kDa protein 4 (Hsp74). Gene ontology analyses reveal that many of them are enriched in binding activity. Kyoto Encyclopedia of Genes and Genomes analysis shows that the top three enriched pathways are ribosome, carbon metabolism, and biosynthesis of amino acids. Molecular and functional investigations show that the high glucose, insulin, and palmitic acid increase the expression and binding of 14-3-3σ and Hsp74 as well as centrosome amplification, all of which are inhibited by knockdown of 14-3-3σ or Hsp74. Moreover, molecular docking analysis shows that the interaction between the 14-3-3σ and the Hsp74 is mainly through hydrophobic contacts and a lesser degree ionic interactions and hydrogen bond by different amino acids residues. In conclusion, the results suggest that the experimental treatment triggers centrosome amplification via upregulations of expression and binding of 14-3-3σ and Hsp74.

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